Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.7.1.2 (nitrate reductase)
 3,861 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hyperglycemia-induced production of oxidative stress results in endothelial cell dysfunction. Previous studies have demonstrated that sphingosine-1-phosphate (S1P) regulates an array of biological activities in endothelial cells mediated by sphingosine-1-phosphate receptors (S1PRs). However, the role of S1PR-mediated signaling pathways in hyperglycemia-induced endothelial cell dysfunction is currently unknown. In the present study, we aimed to explore the role of S1PRs in endothelial cell dysfunction. For this purpose, hyperglycemia-induced oxidative stress was examined using human umbilical vein endothelial cells (HUVECs) cultured with either normal (5.6 mM) or high (25 mM) levels of glucose. The levels of reactive oxygen species (ROS) and nitric oxide (NO) were determined by flow cytometric (FCM) analysis and nitrate reductase, respectively. Endothelial morphogenesis assay was performed in three-dimensional Matrigel. The mRNA and protein expression levels of S1PRs in the HUVECs were determined by RT-qPCR and western blot analysis, respectively. In addition, ROS, NO and endothelial morphogenesis assays were conducted using the high glucose-treated endothelial cells transfected with adenoviral vector expressing exogenous S1PR1 gene (pAd-S1PR1) or with adenoviral vector expressing S1PR2-specific shRNA (pAd-shRNA-S1PR2). The expression levels of S1PR1 and S1PR2 in the endothelial cells treated with high levels of glucose decreased and increased, respectively. However, the effects of high levels of glucose on S1PR3 were minimal. In addition, high levels of glucose enhanced ROS generation and markedly reduced NO generation and morphogenetic responses. Nevertheless, all the aforementioned changes were completely reversed by transfection with pAd-S1PR1 or pAd-shRNA-S1PR2, which increased S1PR1 and decreased S1PR2 expression, respectively. It can thus be concluded that S1PR1 and S1PR2 play crucial roles in hyperglycemia-induced endothelial cell dysfunction.
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PMID:Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction. 2567 82

Endothelial dysfunction is believed the early stage of development of diabetic cardiovascular complications. Sphingosine-1-phosphate (S1P) regulates various biological activities by binding to sphingosine-1-phosphate receptors (S1PRs) including S1PR1-S1PR5. In the present study, the role of S1P receptors in S1P-induced human coronary artery endothelial cells (HCAECs) dysfunction under high glucose condition was investigated and the underlying mechanism was explored. S1PR1-S1PR5 mRNA levels were detected by quantitative Real-time PCR. NO level and polymorphonuclear neutrophils (PMN)-endothelial cells adhesion were measured by nitrate reductase and myeloperoxidase colorimetric method, respectively. Protein levels of endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1(ICAM-1), phosphatidylinositol 3-kinase (PI3K) and Akt were measured by Western blot analysis. S1PR2 were found the predominant S1P receptor expressed in HCAECs exposed to high glucose. NO level and eNOS activity were remarkably decreased, while PMN adhesion, VCAM-1 and ICAM-1 protein levels were increased significantly by S1P treatment in HCAECs exposed to high glucose and normal glucose. Blockage of S1PR2 with specific antagonist JTE-013 and small interfering RNA (siRNA) resulted in enhanced NO level and eNOS activity as well as decreased PMN adhesion, reduced protein levels of VCAM-1 and ICAM-1 induced by S1P. Furthermore, Phosphor-PI3K and phosphor-Akt level were markedly increased by S1PR2 blockade in S1P-treated cells exposed to high glucose, which were suppressed by PI3K inhibitor wortmannin. In conclusion, S1P/S1PR2 mediated endothelial dysfunction partly by inhibiting PI3K/Akt signaling pathway under high glucose condition. S1PR2 blockage could ameliorate endothelial dysfunction which might provide a potential therapeutic strategy for diabetic vascular complications.
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PMID:Sphingosine-1-phosphate receptor 2 mediates endothelial cells dysfunction by PI3K-Akt pathway under high glucose condition. 2692 57